Substituted guanidines have a wide field of use. For example, 1,3-diphenyl guanidines and like substituted guanidines are accelerators for the vulcanization of rubbers. Thus, such guanidine derivatives, when radiolabeled, can be incorporated into a vulcanized rubber object (e.g., a tire tread) and rate of loss of rubber therefrom by water can be monitored by rate of loss of radioactivity. As another example, 1,3-di-(o-tolyl) guanidine may act in an agonistic, antagonistic or inverse agonistic manner in relation to the prototypical sigma benzomorphans and therefore can affect pupil size and heart rate in a direction parallel or opposite that caused by benzomorphans which can be determined by standard tests in laboratory animals. See U.S. Pat. No. 4,709,094, which is incorporated herein by reference.
Similarly, certain tri- and tetra-substituted guanidines, e.g., N-(1-naphthyl)-N'-(3-ethylphenyl)-N'-methyl guanidine, also exhibit exceptionally low binding to the sigma brain receptor. Such compounds can thus be used for treating diseases of the nervous system in which the pathophysiology of the diseases involves excessive excitation of nerve cells by agonists of the glutamate/N-methyl-D-Aspartate (NMDA) receptor. See U.S. patent application Ser. No. 07/663,134, also incorporated herein by reference.
The synthesis of substituted guanidines by reaction of ammonia or amine derivatives with cyanamide derivatives is a well-known reaction. Symmetrical or unsymmetrical N,N'-disubstituted guanidines can be conveniently made by reaction of an appropriate amine with an appropriate cyanamide either by fusion or in a suitable boiling solvent such as chlorobenzene. Safir, S. R. et al. J. Org. Chem. 13: 924 (1948); Gulek, H. W. et al. J. Med. Chem. 12:712 (1969). For example, see Reaction (I) set forth below in which each R.sup.1 and R.sup.2 is aryl or alkyl. ##STR1##
However, preparation of tri- or tetra-substituted guanidines using the same reaction is limited by the lower nucleophilicity of the secondary amines or inversely lower electrophilicity of the substituted cyanamides. Indeed, the reaction of a secondary amine and disubstituted cyanamide is a very low yield synthesis (0-20%) of substituted guanidine even under forcing conditions involving fusion at temperatures as high as 200.degree. C., coupled with difficult product isolation and purification. Thus, it is very difficult and impractical to use Reaction (I) for large scale synthesis of unsymmetrical tetra-substituted guanidines.
Also, the reaction of a monosubstituted amine and a disubstituted cyanamide to produce a trisubstituted cyanamide can be a very low yield synthesis, coupled with difficult product isolation and purification. For example, the yield of N-(1-naphthyl)-N'-(3-ethylphenyl)-N'-methyl guanidine from 1-naphthylamine and N-methyl, N-(3-ethylphenyl) cyanamide is as low as 17%. The reason for the poor yields can be attributed to the steric hindrance offered by the methyl group of N-methyl, N-(3-ethylphenyl) cyanamide to the approach of the nucleophilic amine.